End stage renal disease (ESRD) is the major health problem for patients with type 1 diabetes (T1DM), afflicting about 25%. Unfortunately, during the last 20 years the risk of ESRD due to T1DM in the U.S. population has not declined despite widespread use of reno-protective drugs. Clearly, new knowledge of the causes of renal function decline in T1DM is urgently needed in order to design more effective interventions. From our recent findings it appears that only 30% of patients with T1DM and microalbuminuria (MA) develop clinically significant renal function decline, whereas the rest have stable renal function, as do those without MA. The most interesting aspect of this finding is that the decline for this subset of patients begins with the onset of MA, when renal function is at or above a normal level (average GFR 150 ml/min) and is unrelated to urinary albumin excretion rate within MA or ACE inhibitor treatment. Once initiated, it appears that renal function decline progresses unabated. The main goal of this application is to identify determinants of this early renal function decline and to consider their potential as diagnostic predictors of renal function loss in individuals with T1DM and MA while their renal function is still normal. This application aims to examine the following in the 2nd Joslin Study: 1) The frequency of early renal function decline in 954 patients with T1DM and MA already recruited into the 2nd Joslin Study and who will be followed at least for 4 years; 2) Independent and joint effects of various kidney risk factors on early renal function decline, including a) Intensity of glomerular filtration barrier damage as reflected in urinary excretion of albumin and IgG, b) Intensity of urinary excretion of pro-inflammatory cytokines (TNF-alpha, IL-1beta, INF-gamma, and IL-6), c)Intensity of urinary excretion of chemokines (IL-8, MCP-1, IP-10, and RANTES) considered causes or markers of renal tubulointerstitial damage; 3) Independent and joint effects of systemic risk factors such as HbA1c, total serum cholesterol, serum triglycerides, cigarette smoking, blood pressure and ACE inhibitor treatment on the occurrence of early renal function decline; 4) Genetic determinants of early renal function decline. This will include the following candidate genes: genes previously shown to contribute to susceptibility to ESRD (eNOS, and ENPP1/PC-1), and genes encoding for selected chemokines (IL-8, MCP-1, IP-10, and RANTES) and their receptors (IL8RA, IL8RB, CCR2, CXCR3 and CCR5). If our research is successful, individuals at high risk of renal function loss can be identified and targeted for intervention 5-10 years earlier than currently achievable, possibly with protocols aimed at new therapeutic targets.